Genetic Testing of Non-familial Deaf Patients for CIB2 and GJB2 Mutations: Phenotype and Genetic Counselling

Shaikh, Hina; Waryah, Ali Muhammad; Narsani, Ashok Kumar; Iqbal, Muhammad; Shahzad, Mohsin; Waryah, Yar Muhammad; N, Shaikh; Mahmood, Amber

doi:10.1007/s10528-017-9828-3

Cited by 5 publications

(3 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies in mouse have highlighted the crucial role of CIB2 in the mechanotransduction process and the deleterious effect of this specific missense mutation on hearing (Giese et al, 2017; Michel et al, 2017). Variants of CIB2 have been found in hearing-impaired individuals of Turkish, Caribbean Hispanic, Iranian, Palestinian Arab, European and Dutch origin (Booth et al, 2017; Michel et al, 2017; Patel et al, 2015; Riazuddin et al, 2012; Seco et al, 2016; Shaikh et al, 2017). Together with previously published studies, the CIB2 c.272T>C allele has been found in 85 hearing-impaired Pakistani families (Rehman et al, 2015; Riazuddin et al, 2012; Seco et al, 2016; Shaikh et al, 2017) and is likely to be a founder allele (Riazuddin et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

Rlp

Faridi

et al. 2018

Human Mutation

Self Cite

View full text Add to dashboard Cite

Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 71 (43.6%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

Rlp

Faridi

et al. 2018

Human Mutation

Self Cite

View full text Add to dashboard Cite

show abstract

“…The remaining variants were prioritized according to (i) their predicted deleteriousness scores calculated by the SIFT [21], PolyPhen [22] and MutationTaster [23], (ii) GERP scores [24] to look at the conservation, (iii) the severity of the genetic alteration (e.g., truncation vs missense vs synonymous variant). Cases in which we found pathogenic or likely pathogenic variants in known BBS/RP genes were further investigated by genotyping all family members through Sanger sequencing for the segregation of variants with the disease phenotypes in corresponding families [25].…”

Section: Whole Exome Sequencing Data Analysismentioning

confidence: 99%

Delineating the Spectrum of Genetic Variants Associated with Bardet-Biedl Syndrome in Consanguineous Pakistani Pedigrees

Rao

Nazir

Imtiaz

et al. 2023

Genes

View full text Add to dashboard Cite

This study aimed to find the molecular basis of Bardet-Biedl syndrome (BBS) in Pakistani consanguineous families. A total of 12 affected families were enrolled. Clinical investigations were performed to access the BBS-associated phenotypes. Whole exome sequencing was conducted on one affected individual from each family. The computational functional analysis predicted the variants’ pathogenic effects and modeled the mutated proteins. Whole-exome sequencing revealed 9 pathogenic variants in six genes associated with BBS in 12 families. The BBS6/MKS was the most common BBS causative gene identified in five families (5/12, 41.6%), with one novel (c.1226G>A, p.Gly409Glu) and two reported variants. c.774G>A, Thr259LeuTer21 was the most frequent BBS6/MMKS allele in three families 3/5 (60%). Two variants, c.223C>T, p.Arg75Ter and a novel, c. 252delA, p.Lys85STer39 were detected in the BBS9 gene. A novel 8bp deletion c.387_394delAAATAAAA, p. Asn130GlyfsTer3 was found in BBS3 gene. Three known variants were detected in the BBS1, BBS2, and BBS7 genes. Identification of novel likely pathogenic variants in three genes reaffirms the allelic and genetic heterogeneity of BBS in Pakistani patients. The clinical differences among patients carrying the same pathogenic variant may be due to other factors influencing the phenotype, including variants in other modifier genes.

show abstract

“…Currently, more than 300 mutations in GJB2 have been reported (the Human Gene Mutation Database) [25]. Notably, several alleles have been found to be particularly enriched in certain populations: c.35delG in Europe, America, North Africa, and the Middle East; c.71G>A in India and Pakistan; c.167delT in Ashkenazi Jews; and c.109G>A in East and Southeast Asia [16,[26][27][28]. The contribution of GJB2 mutations to genetic HL varies by ethnicity, but such mutations are the primary cause of congenital severe-toprofound autosomal recessive NSHL (up to 50% worldwide) [29,30].…”

Section: Introductionmentioning

confidence: 99%

Hearing Phenotypes of Patients with Hearing Loss Homozygous for the GJB2 c.235delc Mutation

et al. 2020

View full text Add to dashboard Cite

Hereditary hearing loss is characterized by remarkable phenotypic heterogeneity. Patients with the same pathogenic mutations may exhibit various hearing loss phenotypes. In the Chinese population, the c.235delC mutation is the most common pathogenic mutation of GJB2 and is closely related to hereditary recessive hearing loss. Here, we investigated the hearing phenotypes of patients with hearing loss associated with the homozygous c.235delC mutation, paying special attention to asymmetric interaural hearing loss. A total of 244 patients with the GJB2 c.235delC homozygous mutation encountered from 2007 to 2015 were enrolled. The severity of hearing loss was scaled with the American Speech-Language-Hearing Association (ASHA). Auditory phenotypes were analyzed, and three types of interaural asymmetry were defined based on audiograms: Type A (asymmetry of hearing loss severity), Type B (asymmetry of audiogram shape), and Type C (Type A plus Type B). Of the 488 ears (244 cases) examined, 71.93% (351) presented with profound hearing loss, 14.34% (70) with severe hearing loss, and 9.43% (46) with moderate to severe hearing loss. The most common audiogram shapes were descending (31.15%) and flat (24.18%). A total of 156 (63.93%) of the 244 patients exhibited asymmetric interaural hearing loss in terms of severity and/or audiogram shape. Type A was evident in 14 of these cases, Type B in 106, and Type C in 36. In addition, 211 of 312 ears (67.63%) in the interaural hearing asymmetry group showed profound hearing loss, and 59 (18.91%) exhibited severe hearing loss, with the most common audiogram shapes being flat (27.88%) and descending (22.12%). By contrast, in the interaural hearing symmetry group, profound hearing loss was observed in 140 ears (79.55%), and the most common audiograms were descending (46.59%) and residual (21.59%). Hearing loss associated with the GJB2 c.235delC homozygous mutation shows diverse phenotypes, and a considerable proportion of patients show bilateral hearing loss asymmetry.

show abstract

Genetic Testing of Non-familial Deaf Patients for CIB2 and GJB2 Mutations: Phenotype and Genetic Counselling

Cited by 5 publications

References 44 publications

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

Delineating the Spectrum of Genetic Variants Associated with Bardet-Biedl Syndrome in Consanguineous Pakistani Pedigrees

Hearing Phenotypes of Patients with Hearing Loss Homozygous for the GJB2 c.235delc Mutation

Contact Info

Product

Resources

About